(4R-Cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-acetate is a key intermediate in the preparation of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl]-1-[2-(tetrah ydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide or the salt of the hydroxy acid, [R-(R*,R*)]-2-(4-fluorophenyl)-.beta., .delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid calcium salt (2:1), corresponding to the opened lactone ring of the aforementioned compound described in U.S. Pat. Nos. 4,647,576 and 4,681,893, which are herein incorporated by reference. The aforementioned compound is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and is thus useful as a hypolipidemic and hypocholesterolemic agent.
(4R-Cis)-1,1-dimethylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate may be, in turn, prepared from (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate.
A synthetic procedure for preparing (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate is disclosed in copending U.S. patent application Ser. No. 303,733. The aforementioned procedure involves a linear synthetic route involving 10 steps, including a low temperature (-85.degree. C. to -95.degree. C.) reaction carried out under carefully controlled conditions. The reaction involves reduction of a hydroxy ketone with sodium borohydride and a trialkylborane. Although this reaction provides the target compound in high enantiomeric excess, it is difficult to conduct on a large-scale and employs expensive reagents which are difficult to handle.
The displacement of sulfonates and halides by cyanide is well known in the art. However, such displacements in complex systems, and in particular a system containing a 1,3-dioxane ring, have not been successfully carried out. In point of fact, Sunay, U. and Fraser-Reid, B., Tetrahedron Letters, 27, pages 5335-5338 (1986) reported the failure of such a displacement in a system containing a 1,3-dioxane ring.
Thus, we have surprisingly and unexpectedly found that the nitrile of the present invention, (4R-cis)1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate , can be obtained by a process of displacing various activated sulfonate or halide 1,3-dioxane derivatives with a metal cyanide.
The object of the present invention is an improved, short, efficient, and economical process for the preparation of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate. Thus, the present method avoids the costly, low temperature reaction of the prior method and is amenable to large scale synthesis.